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Nrf2 Contributes to the Weight Gain of Mice During Space Travel

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Nrf2 Contributes to the Weight Gain of Mice During Space Travel ARTICLE https://doi.org/10.1038/s42003-020-01227-2 OPEN Nrf2 contributes to the weight gain of mice during space travel Takafumi Suzuki 1,17, Akira Uruno1,2,17, Akane Yumoto3,17, Keiko Taguchi1,2,4, Mikiko Suzuki 5, Nobuhiko Harada6, Rie Ryoke7, Eriko Naganuma1, Nanae Osanai1, Aya Goto8, Hiromi Suda1, Ryan Browne7, Akihito Otsuki 2, Fumiki Katsuoka2,4, Michael Zorzi 9, Takahiro Yamazaki2, Daisuke Saigusa2, 1234567890():,; Seizo Koshiba2,4, Takashi Nakamura 10, Satoshi Fukumoto11, Hironobu Ikehata1, Keizo Nishikawa12, Norio Suzuki13, Ikuo Hirano2,8, Ritsuko Shimizu2,8, Tetsuya Oishi13, Hozumi Motohashi 14, Hirona Tsubouchi15, Risa Okada3,15, Takashi Kudo15, Michihiko Shimomura3, Thomas W. Kensler 16, Hiroyasu Mizuno3, ✉ ✉ Masaki Shirakawa3, Satoru Takahashi 15, Dai Shiba3 & Masayuki Yamamoto 1,2,4 Space flight produces an extreme environment with unique stressors, but little is known about how our body responds to these stresses. While there are many intractable limitations for in-flight space research, some can be overcome by utilizing gene knockout-disease model mice. Here, we report how deletion of Nrf2, a master regulator of stress defense pathways, affects the health of mice transported for a stay in the International Space Station (ISS). After 31 days in the ISS, all flight mice returned safely to Earth. Transcriptome and metabolome analyses revealed that the stresses of space travel evoked ageing-like changes of plasma metabolites and activated the Nrf2 signaling pathway. Especially, Nrf2 was found to be important for maintaining home- ostasis of white adipose tissues. This study opens approaches for future space research utilizing murine gene knockout-disease models, and provides insights into mitigating space-induced stresses that limit the further exploration of space by humans. 1 Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan. 2 Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan. 3 JEM Utilization Center, Human Spaceflight Technology Directorate, JAXA, Tsukuba, Japan. 4 The Advanced Research Center for Innovations in Next-Generation Medicine (INGEM), Tohoku University, Sendai, Japan. 5 Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Japan. 6 Institute for Animal Experimentation, Tohoku University Graduate School of Medicine, Sendai, Japan. 7 Department of Functional Brain Imaging, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan. 8 Department of Molecular Hematology, Tohoku University Graduate School of Medicine, Sendai, Japan. 9 Department of Molecular Biotechnology and Health Sciences, University of Turin, 10125 Torino, Italy. 10 Division of Molecular Pharmacology & Cell Biophysics, Tohoku University Graduate School of Dentistry, Sendai, Japan. 11 Division of Pediatric Dentistry, Tohoku University Graduate School of Dentistry, Sendai, Japan. 12 Immunology Frontier Research Center, Osaka University, Suita, Japan. 13 Division of Oxygen Biology, Tohoku University Graduate School of Medicine, Sendai, Japan. 14 Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan. 15 Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. 16 Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 17These authors contributed equally: Takafumi Suzuki, Akira Uruno, ✉ Akane Yumoto. email: [email protected]; [email protected] COMMUNICATIONS BIOLOGY | (2020) 3:496 | https://doi.org/10.1038/s42003-020-01227-2 | www.nature.com/commsbio 1 ARTICLE COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-020-01227-2 uring space flight, astronauts experience harsh environ- To elucidate roles that Nrf2 plays in regulating adaptive Dments, including microgravity and high-dose cosmic responses to space stresses, in this study we conducted the one radiation, which affect the homeostasis of physiological month-long space travel of six Nrf2-KO mice and six WT mice. systems in our body1. To investigate how space flight affects health After a 31-day stay in the ISS in 2018, all of the flight mice returned of animals, space mouse experiments have been conducted safely to Earth. Using metabolomic as well as transcriptomic, his- exploiting the International Space Station (ISS) and other oppor- tological, morphometric, and behavioral methodologies, we found tunities2–10. However, it has been difficult to attain live return of that Nrf2 signaling was indeed activated by space stresses in various mice from space or to even realize “space travel” of mice. For tissues. Space stress and Nrf2-deficiency brought about changes in instance, the Italian mice drawer system housed six male mice gene expression and plasma metabolite profiles independently for individually, but more than half of the animals died during habi- the most part, but cooperatively in certain situations. In particular, tation in space8–10. Many of the other preceding space mouse Nrf2 is important for the weight-gain of space mice and main- projects did not attempt live return of the mice from space. tenance of white adipose tissue homeostasis in response to the To achieve live-return of space mice, the Japan Aerospace stresses of month-long space travel. Exploration Agency (JAXA) recently established a fully-equipped mouse experimental system for space flight11. It comprises mouse habitat cage units (HCU), transportation cage units (TCU), and a Results centrifuge-equipped biological experiment facility (CBEF). These Outline of MHU-3 mouse project utilizing Nrf2-KO mice.To apparatuses in combination can house mice individually and study contributions of Nrf2 to the protection of mice against the realize artificial gravity experiments in space. In the first and stresses of travel to and from space, and maintenance of home- second missions utilizing this equipment, referred to as Mouse ostasis during their space stay, we have conducted the MHU-3 Habitat Unit-1 and -2 (MHU-1 and MHU-2 conducted in 2016 project. Male Nrf2-KO mice16 and WT mice were bred and and 2017, respectively), 12 wild-type (WT) male mice were suc- selected for space travel. For this purpose, 60 WT and 60 Nrf2- cessfully launched each time, and all the mice returned safely to KO mice at 8-week-old were delivered to the Kennedy Space Earth after approximately 1 month stays in the ISS11,12. One Center (KSC) 3 weeks prior to launch. These mice were accli- salient finding in these missions is that ageing phenotypes, such matized to individual housing cages. After acclimation, we as reduction of bone density and muscle mass, were markedly selected 12 mice for flight to the ISS based upon their body accelerated during space flight; notably, these phenotypes could weight, levels of food consumption and water intake and the be prevented by housing in space with artificial gravity. phenotypic absence of a hepatic shunt (see “Methods”). It has been shown that various environmental stresses, SpaceX Falcon 14 rocket (SpX14) containing the mice in the including oxidative and toxic chemical (often electrophilic) TCU within the Dragon capsule was launched on April 2, 2018 stresses, activate Nrf2 and downstream signaling pathways13. (GMT) from KSC (Fig. 1a). After arrival at the ISS, mice were Nrf2 is the master transcription factor mitigating oxidative stress. relocated to the HCU by the crew. We used an HCU that Nrf2 induction is well-known to prevent various diseases, accommodates one mouse per cage11,12. Before mice were including cancer, diabetes, and inflammation13. As cosmic returned to Earth, they were transferred back into the TCU and radiation induces oxidative stress1 and mechanical stresses can loaded into the Dragon capsule which subsequently splashed also induce Nrf2 activity14, we hypothesized that space stresses down in the Pacific Ocean offshore from Southern California on may activate the Nrf2 signaling pathway allowing, in turn, for May 5. The TCU was unloaded from the capsule and transported Nrf2 to play important roles in regulating adaptive responses to to Long Beach Port on May 7. All mice were alive upon return these space stresses. Although one preliminary analysis exploiting and were then euthanized and dissected at a laboratory to collect astronaut’s hair samples during space flights showed that tissues after a general health assessment and a series of behavioral expression of NRF2 was decreased in their hair roots during space tests. flight15, the experimental design harbored limitations. Therefore, A ground control (GC) experiment precisely simulated the we decided to address further studies that would provide direct space experiment was conducted at JAXA Tsukuba in Japan from lines of evidence on this point. September 17 to October 20, 2018. Six WT and six Nrf2-KO mice In order to test the hypothesis that Nrf2 contributes to the were individually housed in the same units as the flight adaptive maintenance of animal homeostasis in response to the experiment (FL). Both the TCU and HCU were placed in an stresses of space flight, it was critical to establish space travel of air-conditioned room with a 12-h light/dark cycle. Fan-generated Nrf2 gene-knockout model mice16. To do this, however, we airflow (0.2 m/s) inside the HCU maintained the same conditions needed to overcome various challenges, both technical and reg- as in the FL setting.
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